• Xiao Hong Yu, Chang Qing Cao, Giovanni Martino, Carole Puma, Anne Morinville, Stéphane St-Onge, Étienne Lessard, Martin N Perkins, and Laird Jennifer M A JMA.
• AstraZeneca R&D Montréal, 7171 Frédérick-Banting, Ville Saint-Laurent, Québec, Canada H4S 1Z9 McGill Centre for Research on Pain, McGill University, 3655 Promenade Sir William Osler, Montréal, Québec, Canada H3G 1Y6 Department of Pharmacology & Experimental Therapeutics, McGill University, 3655 Promenade Sir William Osler, Montréal, Québec, Canada H3G 1Y6.
• Pain. 2010 Nov 1; 151 (2): 337-344.

AbstractCannabinoids are analgesic in man, but their use is limited by their psychoactive properties. One way to avoid cannabinoid receptor subtype 1 (CB1R)-mediated central side-effects is to develop CB1R agonists with limited CNS penetration. Activation of peripheral CB1Rs has been proposed to be analgesic, but the relative contribution of peripheral CB1Rs to the analgesic effects of systemic cannabinoids remains unclear. Here we addressed this by exploring the analgesic properties and site of action of AZ11713908, a peripherally restricted CB1R agonist, in rodent pain models. Systemic administration of AZ11713908 produced robust efficacy in rat pain models, comparable to that produced by WIN 55, 212-2, a CNS-penetrant, mixed CB1R and CB2R agonist, but AZ11713908 generated fewer CNS side-effects than WIN 55, 212-in a rat Irwin test. Since AZ11713908 is also a CB2R inverse agonist in rat and a partial CB2R agonist in mouse, we tested the specificity of the effects in CB1R and CB2R knock-out (KO) mice. Analgesic effects produced by AZ11713908 in wild-type mice with Freund's complete adjuvant-induced inflammation of the tail were completely absent in CB1R KO mice, but fully preserved in CB2R KO mice. An in vivo electrophysiological assay showed that the major site of action of AZ11713908 was peripheral. Similarly, intraplantar AZ11713908 was also sufficient to induce robust analgesia. These results demonstrate that systemic administration of AZ11713908, produced robust analgesia in rodent pain models via peripheral CB1R. Peripherally restricted CB1R agonists provide an interesting novel approach to analgesic therapy for chronic pain.Copyright © 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

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